SNS-595 and methods of using the same

ABSTRACT

The present invention relates to SNS-595 and methods of treating cancer using the same.

This application is a continuation of U.S. application Ser. No.14/171,673, filed Feb. 3, 2014, which is a continuation of U.S.application Ser. No. 13/159,258, filed Jun. 13, 2011, issued as U.S.Pat. No. 8,669,270 on Mar. 11, 2014, which is a continuation of U.S.application Ser. No. 11/080,283 filed Mar. 14, 2005, issued as U.S. Pat.No. 7,989,468 on Aug. 2, 2011, which claims priority to U.S. ApplicationNo. 60/553,578 filed Mar. 15, 2004, each of which are incorporatedherein by reference.

PARTIES TO A JOINT RESEARCH AGREEMENT

The subject matter of this application arises in part from a jointresearch agreement between Sunesis Pharmaceuticals, Inc. and DainipponSumitomo Pharma Co., Ltd.

SNS-595 is novel naphthyridine cytotoxic agent that was previously knownas AG-7352 (see e.g., Tsuzuki et al, Tetrahedron-Asymmetry 12: 1793-1799(2001) and U.S. Pat. No. 5,817,669). The chemical name of SNS-595 is(+)-1,4-dihydro-7-[(3S,4S)-3-methoxy-4-(methylamino)-1-pyrrolidinyl]-4-oxo-1-(2-thiazoyl)-1,8-naphthyridine-3-carboxylicacid and has the structure shown below

The present invention relates to pharmaceutical compositions and methodsof using SNS-595 to treat cancer.

DESCRIPTION OF THE FIGURES

FIG. 1 depicts the plasma concentrations of SNS-595 over time among thevarious patient cohorts.

DETAILED DESCRIPTION

In one aspect of the present invention, pharmaceutical composition isprovided comprising:

a) SNS-595 and

b) an acid

in an aqueous solution wherein the pH of the solution is 2-3.5. As usedherein, a numerical range is intended to be inclusive. For example, therange of pH 2-3.5 includes both pH 2 and pH 3.5. In one embodiment, thepH of the composition is 2-3. In another embodiment, the pH of thecomposition is 2.3-2.7. As used herein, an aqueous solution is a liquidcomprising water.

Suitable examples of acids include both organic and inorganic acids suchas acetic acid, ascorbic acid, benzene-sulfonic acid, ethanesulfonicacid, glycolic acid, hydrogen chloride, hydrogen bromide,hydroxyethanesulfonic acid, lactic acid, maleic acid, methanesulfonicacid, proprionic acid, succinic acid, sulfuric acid, trifluoroaceticacid, and toluenesulfonic acid. In one embodiment, the acid ishydrochloric acid, methanesulfonic acid or lactic acid. In anotherembodiment, the acid is methanesulfonic acid.

In another embodiment, the pharmaceutical composition further comprisesa tonicity agent. Suitable examples of a tonicity agent include aminoacids (e.g., alanine and glycine), electrolytes (e.g., sodium chlorideand potassium chloride), monosaccharides (e.g. glucose or galactose),disaccharides (e.g. sucrose) and hexahydric alcohols (e.g., mannitol andsorbitol). In another embodiment, the tonicity agent is sodium chloride,glucose, mannitol, or sorbitol. In another embodiment, the tonicityagent is a hexahydric alcohol. In another embodiment, the tonicity agentis sorbitol.

SNS-595 is a cytotoxic agent for the treatment of cancer. The types ofcancers that can be treated using the inventive methods include but arenot limited to: bladder cancer, breast cancer, cervical cancer, coloncancer (including colorectal cancer), esophageal cancer, head and neckcancer, leukemia, liver cancer, lung cancer (both small cell andnon-small cell), lymphoma, melanoma, myeloma, neuroblastoma, ovariancancer, pancreatic cancer, prostate cancer, renal cancer, sarcoma(including osteosarcoma), skin cancer (including squamous cellcarcinoma), stomach cancer, testicular cancer, thyroid cancer, anduterine cancer.

In another aspect of the invention, a method of using SNS-595 to treat ahuman cancer is provided. The method comprises administering to apatient on the basis of body surface area, a dose of 10 mg/m²-150 mg/m²of SNS-595. Body surface area calculations can be calculated forexample, with the Mosteller formula wherein:BSA (m²)=square root of [(height (cm)×weight (kg)/3600].

In another embodiment, the dose is 10 mg/m²-100 mg/m². In anotherembodiment, the dose is 30 mg/m²-75 mg/m². In another embodiment, thedose is 40 mg/m²-80 mg/m². In another embodiment, the dose is 50mg/m²-90 mg/m².

In another embodiment the dose is 20 mg/m²-30 mg/m². In anotherembodiment the dose is 25 mg/m²-35 mg/m². In another embodiment the doseis 40 mg/m²-50 mg/m². In another embodiment the dose is 45 mg/m²-55mg/m². In another embodiment the dose is 50 mg/m²-60 mg/m². In anotherembodiment the dose is 55 mg/m²-65 mg/m². In another embodiment the doseis 60 mg/m²-70 mg/m². In another embodiment the dose is 65 mg/m²-75mg/m². In another embodiment the dose is 70 mg/m²-80 mg/m². In anotherembodiment the dose is 75 mg/m²-85 mg/m². In another embodiment the doseis 80 mg/m²-90 mg/m². In another embodiment the dose is 85 mg/m²-95mg/m². In another embodiment the dose is 90 mg/m²-100 mg/m².

In another embodiment the dose is 95 mg/m²-105 mg/m². In anotherembodiment the dose is 100 mg/m²-110 mg/m². In another embodiment thedose is 105 mg/m²-115 mg/m². In another embodiment the dose is 110mg/m²-120 mg/m². In another embodiment the dose is 115 mg/m²-125 mg/m².In another embodiment the dose is 120 mg/m²-130 mg/m². In anotherembodiment the dose is 125 mg/m²-135 mg/m². In another embodiment thedose is 130 mg/m²-140 mg/m². In another embodiment the dose is 135mg/m²-145 mg/m². In another embodiment the dose is 140 mg/m²-150 mg/m².

The administered dose of SNS-595 can be delivered simultaneously (e.g. asingle bolus injection) or over a 24-hour period (e.g., continuousinfusion over time or divided bolus doses over time) and is repeateduntil the patient experiences stable disease or regression, or until thepatient experiences disease progression or unacceptable toxicity. Forexample, stable disease for solid tumors generally means that theperpendicular diameter of measurable lesions has not increased by 25% ormore from the last measurement. See e.g., Response Evaluation Criteriain Solid Tumors (RECIST) Guidelines, Journal of the National CancerInstitute 92(3): 205-216 (2000). Stable disease or lack thereof isdetermined by methods known in the art such as evaluation of patientsymptoms, physical examination, visualization of the tumor that has beenimaged using X-ray, CAT, PET, or MRI scan and other commonly acceptedevaluation modalities.

The administered dose of SNS-595 can be expressed in units other than asmg/m². For example, doses can be expressed as mg/kg. One of ordinaryskill in the art would readily know how to convert doses from mg/m² tomg/kg to given either the height or weight of a subject or both (seee.g., http:///www.fda.gov/cder/cancer/animalframe.htm). For example, adose of 10 mg/m²-150 mg/m² for a 65 kg human is approximately equal to0.26 mg/kg-3.95 mg/kg.

In another aspect of the present invention, SNS-595 is administeredaccording to a dosing schedule. In one embodiment, the method comprises:

i) administering a dose of 10 mg/m²-150 mg/m² of SNS-595 to a patient;

ii) waiting a period of at least one day where the subject is notadministered any SNS-595;

iii) administering another dose of 10 mg/m²-150 mg/m² of SNS-595 to thepatient; and,

repeating steps ii)-iii) a plurality of times.

For example, if the waiting period were 6 days, then the initial dose ofSNS-595 is administered on Day 1 (step i); the waiting period is sixdays (step ii); and the following dose of SNS-595 is administered on Day8 (step iii). Other exemplary time periods include 2 days, 3 days, 13days, 20 days, and 27 days. In another embodiment, the waiting period isat least 2 days and steps ii) through iii) are repeated at least threetimes. In another embodiment, the waiting period is at least 3 days andsteps ii) through iii) are repeated at least five times. In anotherembodiment, the waiting period is at least 3 days and steps ii) throughiii) are repeated at least three times. In another embodiment, thewaiting period is at least 3 days and steps ii) through iii) arerepeated at least five times. In another embodiment, the waiting periodis at least 6 days and steps ii) through iii) are repeated at leastthree times. In another embodiment, the waiting period is at least 6days and steps ii) through iii) are repeated at least five times. Inanother embodiment, the waiting period is at least 20 days and steps ii)through iii) are repeated at least three times. In another embodiment,the waiting period is at least 20 days and steps ii) through iii) arerepeated at least five times. In another embodiment, the waiting periodis at least 27 days and steps ii) through iii) are repeated at leastthree times. In another embodiment, the waiting period is at least 27days and steps ii) through iii) are repeated at least five times.

In another embodiment, the dosing method comprises administering aweekly dose of SNS-595 to a subject. In another embodiment, the dosingmethod comprises administering a dose of SNS-595 to a subject every twoweeks. In another embodiment, the dosing method comprises administeringa dose of SNS-595 to a subject every three weeks. In another embodiment,the dosing method comprises administering a dose of SNS-595 to a subjectevery four weeks.

In another embodiment, the dosing method comprises a cycle wherein thecycle comprises administering a dose of SNS-595 to a subject every weekfor three weeks followed by a period of at least two weeks where noSNS-595 is administered to said subject and wherein the cycle isrepeated a plurality of times. In another embodiment, the period whereno SNS-595 is administered is two weeks. In another embodiment, theperiod where no SNS-595 is administered is three weeks.

In another aspect of the invention, a method of treating a solid tumoris provided. The method comprises:

i) administering a dose of 10 mg/m²-100 mg/m² of SNS-595 to a patient;

ii) waiting a period of at least six days where the subject is notadministered any SNS-595;

iii) administering another dose of 10 mg/m²-100 mg/m2 of SNS-595 to thepatient; and,

iv) repeating steps ii)-iii) a plurality of times.

In another aspect of the invention, a method of treating a hematologiccancer such as leukemias and lymphomas is provided. The methodcomprises:

i) administering a dose of 60 mg/m²-150 mg/m² of SNS-595 to a patient;

ii) waiting a period of at least two days where the subject is notadministered any SNS-595;

iii) administering another dose of 60 mg/m²-150 mg/m² of SNS-595 to thepatient; and,

-   -   iv) repeating steps ii)-iii) a plurality of times.

In another aspect of the present invention, a method is providedsupportive care to patients being treated with SNS-595. The methodcomprises:

a) administering to a patient a dose of 10 mg/m²-150 mg/m² of SNS-595and

b) administering a therapeutically effective amount of a supportive careagent.

The supportive care agent is any substance that prevents or manages anadverse effect from SNS-595 treatment and is administered according tothe appropriate dosing regimen for that substance. For example,different supportive care agents for treating nausea have differentdosing regimen. While some are administered prophylactically, others areco-administered with SNS-595 while still others are administered afterthe administration of SNS-595. Illustrative examples of supportive careagents their doses and dosing regimens are found in The Physician's DeskReference.

In one embodiment, the supportive care agent is an antiemetic.Illustrative examples of antiemetics include but are not limited tophenothiazines, butyrophenones, benzodiazapines, corticosteroids,serotonin antagonists, cannabinoids, and NK₁ receptor antagonists.Examples of phenothiazine antiemetics include prochlorperazine andtrimethobenzamide. An example of a butyrophenone antiemetic ishaloperidol. An example of a benzodiazapine antiemetic is lorazepam. Anexample of a corticosteroid antiemetic is dexamethasone. Examples of aserotonin antagonist antiemetic include ondansetron, granisetron, anddolasetron. An example of a cannabinoid antiemetic is dronabinol. Anexample of an NK1 receptor antagonist is aprepitant.

In another embodiment, the antiemetic is prochlorperazine. In anotherembodiment, the antiemetic is prochlorperazine and the therapeuticallyeffective amount is 10 mg. In another embodiment, the antiemetic isprochlorperazine and the therapeutically effective amount is an oraldose of 10 mg before the administration of SNS-595. In anotherembodiment, the antiemetic is prochlorperazine and the therapeuticallyeffective amount is an oral dose of 10 mg every four to six hours asneeded after the administration of SNS-595.

In another embodiment, the antiemetic is dexamethasone. In anotherembodiment, the antiemetic is dexamethasone and the therapeuticallyeffective amount is at least 4 mg. In another embodiment, the antiemeticis dexamethasone and the therapeutically effective amount is an oraldose of 4 mg before the administration of SNS-595. In anotherembodiment, the antiemetic is dexamethasone and the therapeuticallyeffective amount is an oral dose of 8 mg before the administration ofSNS-595. In another embodiment, the antiemetic is dexamethasone and thetherapeutically effective amount is an intravenous dose of between about10 mg and about 20 mg before the administration of SNS-595. In anotherembodiment, the antiemetic is dexamethasone and the therapeuticallyeffective amount is an oral dose of 4 mg every six to twelve hours asneeded after the administration of SNS-595.

In another embodiment, the antiemetic is lorazepam. In anotherembodiment, the antiemetic is lorazepam and the therapeuticallyeffective amount is 1 mg. In another embodiment, the antiemetic islorazepam and the therapeutically effective amount is an oral dose of 1mg before the administration of SNS-595. In another embodiment, theantiemetic is lorazepam and the therapeutically effective amount is anintravenous dose of 1 mg before the administration of SNS-595. Inanother embodiment, the antiemetic is lorazepam and the therapeuticallyeffective amount is an oral dose of 1 mg every four to six hours asneeded after the administration of SNS-595.

In another embodiment, the antiemetic is dolasetron. In anotherembodiment, the antiemetic is dolasetron and the therapeuticallyeffective amount is 100 mg. In another embodiment, the antiemetic isdolasetron and the therapeutically effective amount is an oral dose of100 mg before the administration of SNS-595. In another embodiment, theantiemetic is dolasetron and the therapeutically effective amount is anintravenous dose of 100 mg before the administration of SNS-595.

In another embodiment, the antiemetic is ondansetron. In anotherembodiment, the antiemetic is ondansetron and the therapeuticallyeffective amount is at least 10 mg. In another embodiment, theantiemetic is ondansetron and the therapeutically effective amount is anintravenous dose of 10 mg before the administration of SNS-595. Inanother embodiment, the antiemetic is ondansetron and thetherapeutically effective amount is an intravenous dose of 32 mg beforethe administration of SNS-595.

In another embodiment, the antiemetic is granisetron. In anotherembodiment, the antiemetic is granisetron and the therapeuticallyeffective amount is 10 μg/kg. In another embodiment, the antiemetic isgranisetron and the therapeutically effective amount is an intravenousdose of 10 μg/kg before the administration of SNS-595. In anotherembodiment, the antiemetic is granisetron and the therapeuticallyeffective amount is at least 1 mg. In another embodiment, the antiemeticis granisetron and the therapeutically effective amount is an oral doseof 1 mg before the administration of SNS-595. In another embodiment, theantiemetic is granisetron and the therapeutically effective amount is anoral dose of 2 mg before the administration of SNS-595.

In another embodiment, the antiemetic is aprepitant. In anotherembodiment, the antiemetic is aprepitant and the therapeuticallyeffective amount is at least 80 mg. In another embodiment, theantiemetic is aprepitant and the therapeutically effective amount is anoral dose of 125 mg before the administration of SNS-595. In anotherembodiment, the antiemetic is aprepitant and the therapeuticallyeffective amount is a daily oral dose of 80 mg for at least two daysafter the administration of SNS-595.

In another embodiment, the supportive care agent is a hematopoieticagent. A hematopoietic agent is a molecule that stimulateshematopoiesis. Illustrative examples of hematopoietic agents include butare not limited to granulocyte colony stimulating factor (G-CSF),granulocyte macrophage colony stimulating factor (GM-CSF),erythropoietin and erythropoiesis stimulating protein, and derivativesthereof. Examples of G-CSF include but are not limited to filgrastim andits derivatives including pegfilgrastim. An example of GM-CSF includessargramostim. An example of erythropoietin is epoetin alfa. An exampleof erythropoiesis stimulating protein is darbepoetin alfa.

In another embodiment, the hematopoietic agent is G-CSF. In anotherembodiment, the hematopoietic agent is filgrastim. In anotherembodiment, the hematopoietic agent is filgrastim and thetherapeutically effective amount is at least 4 μg/kg. In anotherembodiment, the hematopoietic agent is filgrastim and thetherapeutically effective amount is a daily dose of at least 4 μg/kg forat least 7 days after the administration of SNS-595. In anotherembodiment, the hematopoietic agent is filgrastim and thetherapeutically effective amount is a daily subcutaneous dose of betweenabout 4 μg/kg and about 8 μg/kg for at least 7 days starting from thethird day after the administration of SNS-595. In another embodiment,the hematopoietic agent is filgrastim and the therapeutically effectiveamount is a daily subcutaneous dose of between about 4 μg/kg and about10 μg/kg for at least 14 days starting from the third day after theadministration of SNS-595.

In another embodiment, the hematopoietic agent is pegfilgrastim. Inanother embodiment, the hematopoietic agent is pegfilgrastim and thetherapeutically effective amount is 6 mg. In another embodiment, thehematopoietic agent is pegfilgrastim and the therapeutically effectiveamount is a daily subcutaneous dose of 6 mg after the administration ofSNS-595. In another embodiment, the hematopoietic agent is pegfilgrastimand the therapeutically effective amount is 100 μg/kg. In anotherembodiment, the hematopoietic agent is pegfilgrastim and thetherapeutically effective amount is a daily dose of 100 μg/kg after theadministration of SNS-595.

In another embodiment, the hematopoietic agent is GM-CSF. In anotherembodiment, the hematopoietic agent is sargramostim. In anotherembodiment, the hematopoietic agent is sargramostim and thetherapeutically effective amount is 250 μg/m². In another embodiment,the hematopoietic agent is sargramostim and the therapeuticallyeffective amount is a daily intravenous or subcutaneous dose of 250μg/m². In another embodiment, the hematopoietic agent is sargramostimand the therapeutically effective amount is a daily intravenous orsubcutaneous dose of 250 μg/m² as needed starting from the third dayafter the administration of SNS-595. In another embodiment, thehematopoietic agent is sargramostim and the therapeutically effectiveamount is a daily intravenous or subcutaneous dose of 250 μg/m² asneeded starting from the tenth day after the administration of SNS-595.

In another embodiment, the hematopoietic agent is erythropoietin. Inanother embodiment, the hematopoietic agent is epoetin alfa. In anotherembodiment, the hematopoietic agent is epoetin alfa and thetherapeutically effective amount is at least 150 units/kg. In anotherembodiment, the hematopoietic agent is epoetin alfa and thetherapeutically effective amount is an intravenous or subcutaneous doseof 150 units/kg three times a week after the administration of SNS-595.In another embodiment, the hematopoietic agent is epoetin alfa and thetherapeutically effective amount is an intravenous or subcutaneous doseof 300 units/kg three times a week after the administration of SNS-595.In another embodiment, the hematopoietic agent is epoetin alfa and thetherapeutically effective amount is 40,000 units. In another embodiment,the hematopoietic agent is epoetin alfa and the therapeuticallyeffective amount is a weekly dose of 40,000 units after theadministration of SNS-595.

In another embodiment, the hematopoietic agent is erytliropoiesisstimulating protein. In another embodiment, the hematopoietic agent isdarbepoetin alfa. In another embodiment, the hematopoietic agent isdarbepoetin alfa and the therapeutically effective amount is betweenabout 1.5 μg/kg and about 4.5 μg/kg. In another embodiment, thehematopoietic agent is darbepoetin alfa and the therapeuticallyeffective amount is a weekly dose of between about 1.5 μg/kg and about4.5 μg/kg.

All cited references are incorporated herein by reference.

EXAMPLE 1

Pharmaceutical Composition Suitable for Injection or IntravenousInfusion

Acidic compositions (<pH 4) provided the appropriate balance ofincreased solubility of SNS-595 and desirable pharmaceutical properties(e.g. increased patient comfort by causing less irritation at thedelivery site). An illustrative example of a suitable compositioncomprises: 10 mg SNS-595 per mL of aqueous solution of 4.5% sorbitolthat is adjusted to pH 2.5 with methanesulfonic acid. One protocol formaking such a solution includes the following for making a 100 mg/10 mLpresentation: 100 mg of SNS-595 and 450 mg D-sorbitol are added todistilled water; the volume is brought up to a volume of 10 mL; and thepH of the resulting solution is adjusted to 2.5 with methanesulfonicacid. The resulting composition is also suitable for lyophilization. Thelyophilized form is then reconstituted with sterile water to theappropriate concentration prior to use.

EXAMPLE 2

Pharmacokinetics of SNS-595 in Cancer Patients

SNS-595 was administered to enrolled patients for up to six cycles. Acycle is defined as a three-week period, with SNS-595 administered onthe first day of each cycle (day 0), followed by at least 21 days ofobservation. SNS-595 was administered to cohorts of at least 3 patientsand dose escalation occurred by sequential cohort. Doses of SNS-595 werelinear with AUC^(oo) and its pharmacokinetic properties were remarkablyconsistent among patients in the same cohort. FIG. 1 depicts the plasmaconcentrations of SNS-595 over time among the various patient cohortsand Table 1 shows the pharmacokinetic parameters derived there from.

TABLE 1 Dose Cmax AUClast AUCINF_obs CI_obs Vz_obs Vss_obs MRTINF_obs(mg/m²) HL (hr) CO (ng/mL) (ng/mL) (hr * ng/mL) (hr * ng/mL) (mL/min/kg)(L/kg) (L/kg) (hr) 3 16.27 152.25 138.80 750.08 1139.55 1.14 1.55 1.4421.96 SD 4.871 82.282 80.566 87.622 263 0.318 0.297 0.277 6.836 6 20.69379.69 347.00 2400.00 2990.29 0.71 1.28 1.24 29.05 SD 0.327 243.598214.96 170.566 245.64 0.153 0.295 0.218 1.15 12 17.81 2888.66 2246.675395.53 6329.15 0.76 1.17 1.07 23.67 SD 3.896 1302.71 1065.145 292.281181.804 0.126 0.258 0.184 5.021 24 16.14 2924.46 2703.33 11133.0212655.32 0.83 1.15 1.06 21.65 SD 2.601 2844.702 2573.02 468.453 851.4580.108 0.124 0.165 5.261 48 21.32 1984.52 2868.00 21098.53 27347.36 0.991.57 1.46 28.90 SD 6.32 189.677 2379.899 9405.346 14382.787 0.616 0.5670.47 8.91 60 17.63 4797.47 4537.50 28112.17 33616.18 0.83 1.20 1.0823.71 SD 4.15 2215.20 1947.89 9127.12 13081.44 0.352 0.37 0.218 6.93

The invention claimed is:
 1. A method for treating ovarian cancercomprising administering to a patient having ovarian cancer a dose of 10mg/m²-150 mg/m² of(+)-1,4-dihydro-7-[(3S,4S)-3-methoxy-4-(methylamino)-1-pyrrolidinyl]-4-oxo-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylicacid.
 2. The method of claim 1 wherein the dose is 10 mg/m²-100 mg/m².3. The method of claim 1 wherein the dose 30 mg/m²-75 mg/m².
 4. Themethod of claim 1 wherein the dose is 40 mg/m²-80 mg/m².
 5. The methodof claim 1 wherein the dose is 50 mg/m²-90 mg/m².
 6. The method of claim1 additionally comprising administering to said patient atherapeutically effective dose of a supportive care agent.
 7. The methodof claim 6 wherein the supportive care agent is an antiemetic.
 8. Amethod for treating ovarian cancer comprising: i) administering a doseof 10 mg/m²-150 mg/m² of(+)-1,4-dihydro-7-[(3S,4S)-3-methoxy-4-(methylamino)-1-pyrrolidinyl]-4-oxo-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylicacid to a patient having ovarian cancer; ii) waiting a period of atleast one day where the patient is not administered any(+)-1,4-dihydro-7-[(3S,4S)-3-methoxy-4-(methylamino)-1-pyrrolidinyl]-4-oxo-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylicacid; iii) administering another dose of 10 mg/m²-150 mg/m² of(+)-1,4-dihydro-7-[(3S,4S)-3-methoxy-4-(methylamino)-1-pyrrolidinyl]-4-oxo-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylicacid to the patient.
 9. The method of claim 8 wherein the period is atleast 2 days.
 10. The method of claim 8 wherein the period is at least 3days.
 11. The method of claim 8 wherein the period is at least 6 days.12. The method of claim 8 wherein the period is at least 13 days. 13.The method of claim 7 wherein the period is at least 20 days.
 14. Themethod of claim 7 wherein the period is at least 27 days.
 15. A methodfor treating ovarian cancer comprising administering a weekly dose of 10mg/m²-150 mg/m² of(+)-1,4-dihydro-7-[(3S,4S)-3-methoxy-4-(methylamino)-1-pyrrolidinyl]-4-oxo-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylicacid to a patient having ovarian cancer.
 16. A method for treatingovarian cancer comprising administering a dose of 10 mg/m²-150 mg/m² of(+)-1,4-dihydro-7-[(3S,4S)-3-methoxy-4-(methylamino)-1-pyrrolidinyl]-4-oxo-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylicacid once every three weeks to a patient having ovarian cancer.
 17. Amethod for treating ovarian cancer comprising a cycle wherein the cyclecomprises administering a dose of 50 mg/m²-110 mg/m² of(+)-1,4-dihydro-7-[(3S,4S)-3-methoxy-4-(methylamino)-1-pyrrolidinyl]-4-oxo-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylicacid to a subject having ovarian cancer once every week for three weeksfollowed by a period of at least two weeks where no(+)-1,4-dihydro-7-[(3S,4S)-3-methoxy-4-(methylamino)-1-pyrrolidinyl]-4-oxo-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylicacid is administered to said subject.